Abstract
The identification of the molecular mechanisms controlling early cell fate decisions in mammals is of paramount importance as the ability to determine specific lineage differentiation represents a significant opportunity for new therapies. Pancreatic Progenitor Cells (PPCs) constitute a regenerative reserve essential for the maintenance and regeneration of the pancreas. Besides, PPCs represent an excellent model for understanding pathological pancreatic cellular remodeling. Given the lack of valid markers of early endoderm, the identification of new ones is of fundamental importance. Both products of the Ink4a/Arf locus, in addition to being critical cell-cycle regulators, appear to be involved in several disease pathologies. Moreover, the locus’ expression is epigenetically regulated in ES reprogramming processes, thus constituting the ideal candidates to modulate PPCs homeostasis. In this study, starting from mouse embryonic stem cells (mESCs), we analyzed the early stages of pancreatic commitment. By inducing mESCs commitment to the pancreatic lineage, we observed that both products of the Cdkn2a locus, Ink4a and Arf, mark a naïve pancreatic cellular state that resembled PPC-like specification. Treatment with epi-drugs suggests a role for chromatin remodeling in the CDKN2a (Cycline Dependent Kinase Inhibitor 2A) locus regulation in line with previous observations in other cellular systems. Our data considerably improve the comprehension of pancreatic cellular ontogeny, which could be critical for implementing pluripotent stem cells programming and reprogramming toward pancreatic lineage commitment.
Highlights
Alterations in PPCs (Pancreatic Progenitor Cells) homeostasis are fundamental to physiological processes, such as organ development and pathological events
These cells were further treated for 4 days with retinoic acid (RA) and Fibroblast growth factor 10 (FGF10) to induce the expression of molecular markers such as such as Hnf6, Sox9, and Nkx6.1 that are typical of the Posterior Foregut Endoderm (PFE)
Are highly enriched in PPCs and represent a good in vitro model to investigate the molecular mechanisms that occur during pancreatic differentiation (Figure 1)
Summary
Alterations in PPCs (Pancreatic Progenitor Cells) homeostasis are fundamental to physiological processes, such as organ development and pathological events. PPCs are essential for the maintenance and regeneration of organs and tissues that exhibit high rates of cell turnover or regenerative reserve. Events associated with an early epithelial-to-mesenchymal transition (EMT) phenotype closely resemble PPCs cellular transition that occurs during normal pancreas embryogenesis [1,2]. Experiments on genetically engineered mice revealed that depletion of progenitor cells leads to acute or delayed failure in tissue homeostasis, limited regenerative potential, and physiological aging [3]. Senescence is a growth-arrest mechanism triggered by different insults to protect cells from hyper-proliferative signals and various forms of stress, representing an important barrier against tumor formation [3].
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